This invention relates to antagonists of melanin-concentrating hormone (MCH) and their use in the treatment of obesity, eating disorders and diabetes, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds.
MCH, a cyclic peptide, was first identified over a decade ago in teleost fish where it appears to regulate color change. More recently, MCH has been the subject of investigation for its possible role as a regulator of eating behavior in mammals. As reported by Shimada et al., Nature, Vol. 396 (Dec. 17 1998), pp. 670-673, MCH-deficient mice have reduced body weight and leanness due to hypophagia (reduced feeding). In view of their findings, it was suggested that antagonists of MCH may be effective for the treatment of obesity. U.S. Pat. No. 5,908,830 discloses a combination therapy for the treatment of diabetes or obesity involving the administration of a metabolic rate increasing agent and a feeding behavior modifying agent, an example of the latter being an MCH antagonist. Further, MCH receptor antagonists may also be useful in the treatment of depression and/or anxiety. Borowksy et al., Nature Medicine, 8, pp. 825-830 (Aug. 1, 2002).
The present invention relates to the compound represented by structural formula I: 
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
Ar1 is aryl, heteroaryl, (R7)p-substituted aryl or (R7)p-substituted heteroaryl, wherein p is a number from 1 to 5 and when p is more than 1, each R7 can be the, same or different and each R7 is hydrogen or independently selected from the group consisting of OH, alkoxy, CN, halogen, NR8R9, C(O)NR8R9, N(R8)C(O)R5, N(R8)S(O2)R5, S(O2)NR8R9, C(O)OR8, OCF3, CF3, S(O2)R5 and C(O)R5, or two adjacent R7 can be joined together to form an alkylenedioxy selected from 
or when Ar1 is an (R7)p-substituted aryl, where R7 and the phenyl ring to which it is shown attached in Formula I can be bridged by Y as shown by 
R1 is H, alkyl, aryl, aralkyl, aryloxyalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, (styrenyl)methyl, heteroaralkyl, cycloalkylalkyl, heterocyclyl, cycloalkyl, wherein each of said alkyl, aralkyl, aryloxyalkyl, hydroxyalkyl, alkoxyalkyl, heteroaralkyl, cycloalkylalkyl, heterocyclyl and cycloalkyl can be unsubstituted or optionally substituted with one or more R7 moieties which can be the same or different, xe2x80x94S(O2)NR8R9, S(O2)R5, C(O)OR8, C(O)R5, C(O)NR8R9, (R7)p-substituted aryl or (R7)p-substituted heteroaryl, wherein p is a number from 1 to 5 and when p is more than 1, each R7 can be the same or different and each R7 is hydrogen or independently selected from the group consisting of alkyl, cycloalkyl, OH, alkoxy, CN, halogen, heteroaryl, OC(O)OH; aryloxy, NR8R9, C(O)NR8R9, N(R8)C(O)R5, N(R8)S(O2)R5, S(O2)NR8R9, C(O)OR8, OCF3, CF3, SR5, S(O2)R5 and C(O)R5,
or two adjacent R7 can be joined together to form an alkylenedioxy selected from 
R2, R3, R8 and R9 can each be the same or different and each independently H or alkyl;
or R2 and R3 together are alkylene and with the carbon to which they are attached form a 3 to 7 membered ring;
R4 is H, alkyl, aralkyl, R5C(O), R5S(O2) or 
R5 is alkyl or aryl;
R6 is alkyl, aralkyl or (R7)p-substituted aralkyl, wherein p is a number from 1 to 5 and when p is more than 1, each R7 can be the same or different and each R7 is hydrogen or independently selected from the group consisting of OH, alkoxy, CN, halogen, NR8R9, C(O)NR8R9, N(R8)C(O)R5, N(R8)S(O2)R5, xe2x80x94S(O2)NR8R9, C(O)OR8, OCF3, CF3, S(O2)R5 and C(O)R5,
R10 is aryl, heteroaryl, (R7)p-substituted aryl or (R7)p-substituted heteroaryl, wherein p is a number from 1 to 5 and when p is more than 1, each R7 can be the same or different and each R7 is hydrogen or independently selected from the group consisting of OH, alkoxy, CN, halogen, NR8R9, C(O)NR8R9, N(R8)C(O)R5, N(R8)S(O2)R5, S(O2)NR8R9, C(O)OR8, OCF3, CF3, S(O2)R5, C(O)R5 and heterocycloalkyl or R10 is an alkylene or heteroalkylene where said alkylene or heteroalkylene is attached to the N of NR10 to form a heterocyclyl ring selected from the group consisting of 
X is N(R4), O, S, Sxe2x86x92O, S(O2), C(O) or CH2;
Y is O, CH2, C(O), N(H), N(R6) or S;
k is 0, 1 or 2;
m is 0, 1 or 2;
n is 0 or 2; and
wherein each of said alkyl, alkylene, heteroalkylene, aryl, aralkyl, alkoxy, arylyoxy, aryloxyalkyl, hydroxyalkyl, alkoxyalkyl, heterocyclyl, heterocycloalkyl, heteroaryl, heteroaralkyl, cycloalkylalkyl, heterocyclyl and cycloalkyl can be unsubstituted or optionally substituted with one or more R7 moieties which can be the same or different.
This invention is also directed to pharmaceutical compositions for the treatment of metabolic disorders such as obesity, and eating disorders such as hyperphagia. In one aspect, this invention is also directed to pharmaceutical compositions for the treatment of obesity which comprise an obesity treating amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier.
The present invention relates to compounds that are represented by structural formula I, or a pharmaceutically acceptable salt or solvate, wherein the various moieties are as described above.
The compounds of formula I can be administered as racemic mixtures or enantiomerically pure compounds.
A preferred group of compounds are compounds of formula Ia 
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
q is 1 or 2;
R1 is H, alkyl or cycloalkyl;
R4 is H or alkyl; and
Z is 1 or 2 substituents which can be the same or different and independently selected from the group consisting of halogen, CF3 and OCF3.
Another preferred embodiment is a compound of formula Ib: 
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
q is 1 or 2;
Z is 1 or 2 substituents which can be the same or different and independently selected from the group consisting of halogen, CF3 and OCF3.
A further preferred embodiment is a compound of formula Ic: 
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
q is 1 or 2;
R is H, alkyl or cycloalkyl; and
Z is 1 or 2 substituents which can be the same or different and independently selected from the group consisting of halogen, CF3 and OCF3.
A further preferred embodiment is a compound of formula Id: 
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
q is 1 or 2;
R1 is independently selected from the group consisting of H, alkyl and cycloalkyl; and
Z is 1 or 2 substituents which can be the same or different and independently selected from the group consisting of halogen, CF3 and OCF3.
A further preferred embodiment is a compound of formula Ie: 
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
q is 1 or 2;
Z is 1 or 2 substituents which can be the same or different and independently selected from the group consisting of Cl, CF3 and F.
A further preferred embodiment is a compound of formula If 
or a pharmaceutically acceptable salt or solvate of said compound, wherein
R is selected from the group consisting of CH3C(O), CH3S(O2), CH3CH2OC(O), (CH3CH2)2NC(O), (CH3)2NS(O2), CH3CH2NHS(O2) and cyclopropylmethyl.
A set of preferred compounds are listed below in Table 1.
Except where stated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of xe2x80x9calkylxe2x80x9d applies to xe2x80x9calkylxe2x80x9d as well as to the xe2x80x9calkylxe2x80x9d portions of xe2x80x9calkoxyxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d etc.
As used above, and throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cPatientxe2x80x9d includes both human and other animals.
xe2x80x9cMammalxe2x80x9d means humans and other mammalian animals.
xe2x80x9cAlkylxe2x80x9d means an aliphatic hydrocarbon group, which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. xe2x80x9cLower alkylxe2x80x9d means an alkyl group having about 1 to about 6 carbon atoms in the chain, which may be straight or branched. The term xe2x80x9csubstituted alkylxe2x80x9d means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, xe2x80x94cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, xe2x80x94NH(alkyl), xe2x80x94NH(cycloalkyl), xe2x80x94N(alkyl)2, carboxy and xe2x80x94C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group comprising at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means an alkenyl group having about 2 to about 6 carbon atoms in the chain, which may be straight or branched. The term xe2x80x9csubstituted alkenylxe2x80x9d means that the alkenyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, xe2x80x94cycloalkyl, cyano, and alkoxy. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, and 3-methylbut-2-enyl.
xe2x80x9cAlkynylxe2x80x9d means an aliphatic hydrocarbon group comprising at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. xe2x80x9cLower alkynylxe2x80x9d means an alkynyl group having about 2 to about 6 carbon atoms in the chain, which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl and 2-butynyl. The term xe2x80x9csubstituted alkynylxe2x80x9d means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and xe2x80x94cycloalkyl.
xe2x80x9cAlkylenexe2x80x9d means an alkanediyl group commonly having free valencies on two carbon atoms. Non-limiting examples include methylene, ethylene, propylene and the like. The term xe2x80x9csubstituted alkylenexe2x80x9d means that the alkylene group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, xe2x80x94cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, xe2x80x94NH(alkyl), xe2x80x94NH(cycloalkyl), xe2x80x94N(alkyl)2, carboxy and xe2x80x94C(O)Oxe2x80x94alkyl.
xe2x80x9cArylxe2x80x9d means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be unsubstituted or substituted on the ring with one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, xe2x80x94OCF3, xe2x80x94OCOalkyl , xe2x80x94OCOaryl, xe2x80x94CF3, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, haloalkyl, haloalkoxy, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, xe2x80x94cycloalkyl and heterocyclyl. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. The xe2x80x9carylxe2x80x9d group can also be substituted by linking two adjacent carbons on its aromatic ring via a combination of one or more carbon atoms and one or more oxygen atoms such as, for example, methylenedioxy, ethylenedioxy, and the like.
xe2x80x9cArylenexe2x80x9d means a bivalent group derived from an aromatic hydrocarbon by removal of a hydrogen atom from two ring carbon atoms. Non-limiting examples include phenylene and the like.
xe2x80x9cAlkylenedioxyxe2x80x9d means a combination of one or more carbon atoms and one or more oxygen atoms such as the following non-limiting examples that include methylenedioxy, ethylenedioxy, and the like.
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl group comprising about 5 to about 14 carbon atoms, preferably about 5 to about 10 carbon atoms, in which one or more of the carbon atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 carbon atoms.
xe2x80x9cHeteroarylxe2x80x9d means an aromatic monocyclic or multicyclic ring system (fused as well as connected by bond) comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The xe2x80x9cheteroarylxe2x80x9d can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, xe2x80x94cycloalkyl, cycloalkenyl and heterocyclyl. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl, and the like.
xe2x80x9cHeteroalkylenexe2x80x9d means a difunctional group obtained by removal of a hydrogen atom from an heteroalkyl group that is defined above.
xe2x80x9cHeteroarylenexe2x80x9d means a bivalent group derived from a heterocyclic aromatic compound by removal of a hydrogen atom from two ring carbon atoms such as, for example, the bivalent group derived from pyridine, pyrrole and the like.
xe2x80x9cAralkylxe2x80x9d means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and a naphthlenylmethyl. The bond to the parent moiety is through the alkyl. The term xe2x80x9csubstituted aralkylxe2x80x9d means that the aralkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, xe2x80x94cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, xe2x80x94NH(alkyl), xe2x80x94NH(cycloalkyl), xe2x80x94N(alkyl)2, carboxy and xe2x80x94C(O)O-alkyl.
xe2x80x9cAlkylarylxe2x80x9d means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl groups is tolyl. The bond to the parent moiety is through the aryl.
xe2x80x9cCycloalkylxe2x80x9d means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl and heterocyclyl. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, tetrahydronapthalenyl, indanyl, norbornyl, adamantyl and the like.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.
xe2x80x9cHalogenxe2x80x9d means fluorine, chlorine, bromine or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.
xe2x80x9cHaloalkylxe2x80x9d means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl and heterocyclyl. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
xe2x80x9cHeterocyclylxe2x80x9d or xe2x80x9cheterocycloalkylxe2x80x9d means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl and heterocyclyl. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, pyranyl, tetrahydrothiophenyl, morpholinyl and the like.
xe2x80x9cAralkenylxe2x80x9d means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl group. Non-limiting examples of suitable aralkenyl groups include 2-phenethenyl and 2-naphthylethenyl. The bond to the parent moiety is through the alkenyl.
xe2x80x9cHeteroaralkylxe2x80x9d means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl. The xe2x80x9cheteroaralkylxe2x80x9d can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, xe2x80x94cycloalkyl, cycloalkenyl and heterocyclyl.
xe2x80x9cHeteroaralkenylxe2x80x9d means an heteroaryl-alkenyl- group in which the heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl group. Non-limiting examples of suitable heteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and 2-(quinolin-3-yl)ethenyl. The bond to the parent moiety is through the alkenyl.
xe2x80x9cAlkoxyalkylxe2x80x9d means an alkoxy-alkyl- group in which alkyl and alkoxy are as previously defined. Non-limiting examples of suitable alkoxyalkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl and ethoxyethyl.
xe2x80x9cAryloxyalkylxe2x80x9d means aryloxy-alkyl- group in which alkyl and aryloxy are as previously defined. Non-limiting examples of suitable aryloxyalkyl groups include phenyloxymethyl, phenyloxymethyl and benzyloxymethyl.
xe2x80x9cHydroxyalkylxe2x80x9d means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94C(O)xe2x80x94, alkylxe2x80x94C(O)xe2x80x94, alkenylxe2x80x94C(O)xe2x80x94, alkynylxe2x80x94C(O)xe2x80x94, cycloalkyl-C(O)xe2x80x94, cycloalkenyl-C(O)xe2x80x94, or cycloalkynyl-C(O)xe2x80x94 group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, and cyclohexanoyl.
xe2x80x9cAroylxe2x80x9d means an aryl-C(O)xe2x80x94 group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy and isopropoxy. The alkyl group is linked to an adjacent moiety through the ether oxygen. The term xe2x80x9csubstituted alkoxyxe2x80x9d means that the alkyl portion of the alkoxy group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, xe2x80x94cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, xe2x80x94NH(alkyl), xe2x80x94NH(cycloalkyl), xe2x80x94N(alkyl)2, carboxy and xe2x80x94C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl.
xe2x80x9cAryloxyxe2x80x9d means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
xe2x80x9cAlkylaminoxe2x80x9d means an xe2x80x94NH2 or xe2x80x94NH3+ group in which one or more of the hydrogen atoms on the nitrogen is replaced by an alkyl group as defined above.
xe2x80x9cCycloalkylalkylxe2x80x9d means a cycloalkylalkyl group in which the cycloalkyl and alkyl groups are as previously described. The bond to the parent moiety is through the alkyl group.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio. The bond to the parent moiety is through the sulfur.
xe2x80x9cArylthioxe2x80x9d means an aryl-Sxe2x80x94 group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.
xe2x80x9cAralkylthioxe2x80x9d means an aralkyl-Sxe2x80x94 group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkoxy group defined earlier linked to an adjacent moiety through a carbonyl. Non-limiting examples of alkoxycarbonyl groups include xe2x80x94C(O)xe2x80x94CH3, xe2x80x94C(O)xe2x80x94CH2CH3 and the like.
xe2x80x9cAralkoxycarbonylxe2x80x9d means an aralkylxe2x80x94Oxe2x80x94C(O)xe2x80x94 group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.
xe2x80x9cAlkylsulfonylxe2x80x9d means an alkyl-S(O2)xe2x80x94 group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
xe2x80x9cAlkylsulfinylxe2x80x9d means an alkyl-S(O)xe2x80x94 group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfinyl.
xe2x80x9cArylsulfonylxe2x80x9d means an aryl-S(O2)xe2x80x94 group. The bond to the parent moiety is through the sulfonyl.
xe2x80x9cArylsulfinylxe2x80x9d means an aryl-S(O)xe2x80x94 group. The bond to the parent moiety is through the sulfinyl.
The term xe2x80x9coptionally substitutedxe2x80x9d means optional substitution with the specified groups, radicals or moieties.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Solvates of the compounds of the invention are also contemplated herein. xe2x80x9cSolvatexe2x80x9d means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. xe2x80x9cSolvatexe2x80x9d encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. xe2x80x9cHydratexe2x80x9d is a solvate wherein the solvent molecule is H20.
xe2x80x9cEffective amountxe2x80x9d or xe2x80x9ctherapeutically effective amountxe2x80x9d is meant to describe an amount of compound of the present invention effective to treat a mammal (e.g., human) having a disease or condition mediated by MCH, and thus producing the desired therapeutic effect.
The compound of formula I forms salts which are also within the scope of this invention. Reference to a compound of formula I, herein is understood to include reference to salts thereof, unless otherwise indicated. The term xe2x80x9csalt(s)xe2x80x9d, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (xe2x80x9cinner saltsxe2x80x9d) may be formed and are included within the term xe2x80x9csalt(s)xe2x80x9d as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compound of the formula I may be formed, for example, by reacting a compound of formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulforiates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates, and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food and Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of formula I, and salts and solvates thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts and solvates of the compounds), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms xe2x80x9csaltxe2x80x9d, xe2x80x9csolvatexe2x80x9d and the like, is intended to equally apply to the salt and solvate of enantiomers, stereoisomers, rotamers, tautomers or racemates of the inventive compounds.
When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As a general note to all the Tables that are attached hereto as well as to the Description, Examples and Schemes in this application, any open-ended nitrogen atom with unfulfilled valence in the chemical structures herein refers to NH, or in the case of a terminal nitrogen, xe2x80x94NH2. Similarly, any open-ended oxygen atom with unfulfilled valence in the chemical structures herein refers to xe2x80x94OH and any open-ended carbon atom with unfilled valence is appropriately filled with xe2x80x94H.
Compounds of formula I can be highly selective, high affinity Melanin Concentrating Hormone (MCH) receptor antagonists useful for the treatment of obesity.
Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition mediated by MCH by administering a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound to the mammal.
A preferred dosage is about 0.001 to 100 mg/kg of body weight/day of the compound of formula I. An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound.
Another aspect of this invention is directed to a method of treating obesity comprising administering to a mammal in need of such treatment a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound.
Another aspect of this invention is directed to a method for treating eating and metabolic disorders such as bulimia and anorexia comprising administering to a mammal a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound.
Another aspect of this invention is directed to a method for treating hyperlipidemia comprising administering to a mammal a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound.
Another aspect of this invention is directed to a method for treating cellulite and fat accumulation comprising administering to a mammal a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound.
Another aspect of this invention is directed to a method for treating type II diabetes comprising administering to a mammal a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound.
In addition to the xe2x80x9cdirectxe2x80x9d effect of the compounds of this invention on the MCH subtype, there are diseases and conditions that will benefit from the weight loss such as insulin resistance, impaired glucose tolerance, Type II Diabetes, hypertension, hyperlipidemia, cardiovascular disease, gall stones, certain cancers, and sleep apnea.
Another aspect of this invention is directed to a method for treating mental disorders such as major depression, manic depression, anxiety, schizophrenia and sleep disorders, comprising administering to a mammal a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound.
This invention is also directed to pharmaceutical compositions which comprise at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable carrier.
This invention is also directed to pharmaceutical compositions for the treatment of obesity which comprise an obesity treating amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable carrier.
Compounds of formula I, can be produced by processes known to those skilled in the art using either solution phase or solid phase synthesis as shown in the following reaction schemes, in the preparations and examples below.
A preferred group of compounds are those listed below in Table 1. or a pharmaceutically acceptable salt or solvate of said compound.
Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition mediated by MCH by administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt of said compound to the mammal.
A preferred dosage is about 0.001 to 100 mg/kg/day of the formula I compound. An especially preferred dosage is about 0.01 to 25 mg/kg/day of a compound of formula I, or a pharmaceutically acceptable salt of said compound.
Another aspect of this invention is directed to a method of treating obesity comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt of said compound.
Another aspect of this invention is directed to a method for treating metabolic disorders such as obesity and eating disorders such as bulimia and anorexia comprising administering to a mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt of said compound.
Another aspect of this invention is directed to a method for treating hyperlipidemia comprising administering to a mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt of said compound.
Another aspect of this invention is directed to a method for treating cellulite and fat accumulation comprising administering to a mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt of said compound.
Another aspect of this invention is directed to a method for treating type II diabetes comprising administering to a mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt of said compound.
In addition to the xe2x80x9cdirectxe2x80x9d effect of the compounds of this invention on the MCH subtype, there are diseases and conditions that will benefit from the weight loss such as insulin resistance, impaired glucose tolerance, Type II Diabetes, hypertension, hyperlipidemia, cardiovascular disease, gall stones, certain cancers, and sleep apnea.
This invention is also directed to pharmaceutical compositions which comprise an amount of a compound of formula I, or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier therefor.
This invention is also directed to pharmaceutical compositions for the treatment of obesity which comprise an obesity treating amount of a compound of formula, I, a or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier therefor.
Compounds of formula I can be produced by processes known to those skilled in the art using either solution phase or solid phase synthesis as shown in the following reaction schemes, in the preparations and examples below.
Compounds of formulas Ia, Ib and Ic, are prepared according to the method described in Scheme 1;
These novel compounds are potent MCH antagonists and also selective against other receptors, such as M2 receptor, h-HT transporter.
All stereoisomers and tautomeric forms of these compounds are contemplated. Compounds of formulas Ia, Ib and Ic can be prepared from 4-(4-bromophenyl) piperidinol (Scheme 1). 
Compounds of formula Id can be prepared from 4-(4-bromophenyl) piperidinol (Scheme 2). 
A number of compounds where X is an alkylene, are synthesized as seen in schemes 3 and 4. 
Other related routes/chemistry are also contemplated.
Yet another aspect of this invention are combinations of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound and at least one compound from the compounds as illustrated below.
Accordingly, another aspect of this invention is a method for treating obesity comprising administering to a mammal (e.g., a female or male human)
a. an amount of a first compound, said first compound being a compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound; and
b. an amount of a second compound, said second compound being an antiobesity and/or anorectic agent such as a xcex23 agonist, a thyromimetic agent, an anoretic agent, or an NPY antagonist wherein the amounts of the first and second compounds result in a therapeutic effect.
This invention is also directed to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising at least one first compound, said first compound being a compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound
a second compound, said second compound being an antiobesity and/or anorectic agent such as a xcex23 agonist, a thyromimetic agent, an anoretic, or an NPY antagonist; and/or optionally a pharmaceutical carrier, vehicle or diluent.
Another aspect of this invention is a kit comprising:
a. an amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier, vehicle or diluent in a first unit dosage form;
b. an amount of an antiobesity and/or anorectic agent such as a xcex23 agonist, a thyromimetic agent, an anoretic agent, or an NPY antagonist and a pharmaceutically acceptable carrier, vehicle or diluent in a second unit dosage form; and
c. means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.
Preferred antiobesity and/or anorectic agents (taken singly or in any combination thereof) in the above combination methods, combination compositions and combination kits are:
phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake inhibitor (such as sibutramine), a sympathomimetic agent, a serotonergic agent (such as dexfenfluramine or fenfluramine), a dopamine agonist (such as bromocriptine), a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocyte-stimulating hormone analog, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, the OB protein (hereinafter referred to as xe2x80x9cleptinxe2x80x9d), a leptin analog, a leptin receptor agonist, a galanin antagonist or a GI lipase inhibitor or decreaser (such as orlistat). Other anorectic agents include bombesin agonists, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the glucagon-like peptide-1 receptor such as Exendin and ciliary neurotrophic factors such as Axokine.
Another aspect of this invention is a method of treating diabetes comprising administering to a mammal (e.g., a female or male human)
a. an amount of a first compound, said first compound being a compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound; and
b. an amount of a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide wherein the amounts of the first and second compounds result in a therapeutic effect.
This invention is also directed to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound;
a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone, or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide; and optionally a pharmaceutical carrier, vehicle or diluent.
Another aspect of this invention is a kit comprising:
a. an amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier, vehicle or diluent in a first unit dosage form;
b. an amount of an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone, or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide and a pharmaceutically acceptable carrier, vehicle or diluent in a second unit dosage form; and
c. means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 50 mg/day, in two to four divided doses.
This invention is also directed to pharmaceutical compositions for the treatment of metabolic disorders such as obesity, and eating disorders such as hyperphagia.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington""s Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
The compounds of this invention may also be delivered subcutaneously.
Preferably the compound is administered orally.
The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art.
Where NMR data are presented, 1H spectra were obtained on either a Varian VXR-200 (200 MHz, 1H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz) and are reported as ppm down field from Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically. Where LC/MS data are presented, analyses was performed using an Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC column: Altech platinum C18, 3 micron, 33 mmxc3x977 mm ID; gradient flow: 0 minxe2x80x9410% CH3CN, 5 minxe2x80x9495% CH3CN, 7 minxe2x80x9495% CH3CN, 7.5 minxe2x80x9410% CH3CN, 9 minxe2x80x94stop. The retention time and observed parent ion are given.
The following solvents and reagents may be referred to by their abbreviations in parenthesis:
Thin layer chromatography (TLC);
ethyl acetate (AcOEt or EtOAc);
di-t-butyl carbonate (BOC2O);
trifluoroacetate (TFA);
titanium tetraisoproposice (Ti(O-iPr)4;
N,Nxe2x80x2-diisopropylethylamine (iPr2NEt);
triethylamine (Et3N or TEA);
butoxycarbonyl (n-Boc or Boc);
1,2-dimethoxyethane (DME);
1,2-dichloroethane (DCE);
acetic acid (AcOH);
trifluoroacetic anhydride (TFAA);
1-hydroxybenzotriazole (HOBt);
1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCl);
m-chloroperbenzoic acid (MCPBA);
triethylamine (Et3N);
4-dimethylaminopyridine (DMAP)
tert-butoxycarbonyl (Boc);
triethylamine (TEA);
nuclear magnetic resonance spectroscopy (H NMR);
liquid chromatography mass spectrometry (LCMS);
high resolution mass spectrometry (HRMS);
hexane (hex);
milliliters (mL);
millimoles (mmol);
microliters (xcexcl);
grams (g);
milligrams (mg);
room temperature (ambient) about 25xc2x0 C. (rt).